DESCRIPTION: (Verbatim from the applicant's abstract) Trauma and hemorrhagic shock are one of the major causes of acute lung injury in humans. Twenty to twenty-five percent of patients with severe trauma develop acute lung injury, and trauma is the second most common cause of acute lung injury after sepsis. Upregulation of alveolar epithelial fluid transport by endogenous catecholamines is a major mechanism that prevents alveolar flooding after hemorrhagic shock. However, after severe hemorrhage, this protective mechanism is abolished by the development of an oxidative stress to the alveolar epithelium. The oxidative stress to this lung barrier is caused by the release of a large quamtity of nitric oxide (NO) and radical oxygen species that directly alter the function of membrane proteins involved in the beta-adrenergic receptor-cAMP signaling pathway in the alveolar epithelium and by the sequestration of neutrophils in the lung that amplify oxidative stress in the alveolar epithelium. The heat shock or stress response is a highly conserved cellular defense mechanism characterized by the increased expression of stress proteins that "allows the cells to withstand a subsequent lethal insult, a phenomenon referred as "thermotolerance" or "preconditioning." Stress preconditioning with heat has been shown to protect against ischemia-reperfusion injury to the lung, although the mechanisms of protection are poorly understood. Our preliminary data indicated that induction of thermotolerance either with heat or non-thermal stimulus restored normal alveolar epithelial fluid transport after severe hemorrhage in rats. Therefore, we propose to test the hypothesis that the protection against oxidative stress to the alveolar epithelium provided by stress preconditioning with heat is mediated by: (a) a decrease of the inflammatory response in the lung by inhibition of expression of proinflammatory mediators (NO, peroxynitrite) that directly inhibit ion transport across the alveolar epithelium (aim 1); (b0 a decrease in the neutrophil sequestration in lung after severe hemorrhage by decreasing the release of neutrophils from the bone marrow and by increasing the rate of neutrophil apoptosis, as well as by decreasing the expression of adhesion molecules on the surface of the lung endothelium and the airspace release of chemokines CINC-1 and/or MIP-2. (aim 2). In aim 3 of this proposal we will explore how stress preconditioning ( using clinically relavant strategies, such as geldanamycin or direct inducers of Hsp 32 expression), protects against oxidative stress to the alveolar epithelium after hemorrhage.